Schizophrenia is a devastating disease that affects approximately 1% of the world's population and is characterized by a constellation of symptoms that includes hallucinations and delusions (positive symptoms), antisocial behavior and blunted emotions (negative symptoms), and deficits in working memory, executive function, and learning and memory (cognitive symptoms). One of the best known genetic predictors of schizophrenia is the microdeletion disorder 22q11 deletion syndrome (22q11DS). This syndrome is caused by the hemizygous deletion of a 1.5- to 3-megabase region of the q arm of chromosome 22, resulting in the haploinsufficiency of 30 to 40 genes (Burn, et al. (1993) J. Med. Genet. 30:822; Ryan, et al. (1997) J. Med. Genet. 34:798; Scambler, et al. (2000) Hum. Mol. Genet. 9:2421; Oskarsdottir, et al. (2004) Arch. Dis. Child 89:148; Scambler, et al. (1992) Lancet 339:1138). Approximately 30% of children with 22q11DS experience schizophrenia or schizoaffective disorder during adolescence or early adulthood (Chow, et al. (2006) Schizophr. Res. 87:270; Pulver, et al. (1994) J. Nerv. Ment. Dis. 182:476; Bassett, et al. (2005) Am. J. Med. Genet. 138:307). Symptoms of 22q11DS-related schizophrenia are indistinguishable from those of the idiopathic disease (Pulver, et al. (1994) supra; Chow, et al. (2006) supra; Murphy, et al. (1999) Arch. Gen. Psychiatry 56:940), suggesting that the biological mechanisms involved in schizophrenia arising from the 22q11.2 deletion are the same as those involved in non-deletion-related schizophrenia.
Cognitive deficits are central to schizophrenia and are among the least treatable symptoms of the disease (Gold (2004) Schizophr. Res. 72:21; Green (1996) Am. J. Psychiatry 153:321; Green, et al. (2000) Schizophr. Bull. 26:119). These symptoms have been linked, in part, to the hippocampus (Heckers, et al. (1998) Nat. Neurosci. 1:318; Tamminga, et al. (2010) Am. J. Psychiatry 167:1178; Weinberger (1999) Biol. Psychiatry 46:3), a brain region well-studied for its role in learning and memory. Mechanisms of hippocampal learning and memory have been thoroughly characterized using animal models. Synaptic plasticity at excitatory synapses has emerged as a cellular mechanism of hippocampus-related learning and memory (Martin, et al. (2000) Annu. Rev. Neurosci. 23:649; Milner, et al. (1998) Neuron 20:445) and provides an excellent means to probe cellular events related to cognition in animal models of schizophrenia.
The 22q11DS-critical region of human chromosome 22 is largely conserved on mouse chromosome 16, allowing for the generation of 22q11DS mouse models. The Df(16)1/+ mouse carries a hemizygous deletion of 23 genes in the syntenic region of mouse chromosome 16 (Lindsay, et al. (1999) Nature 401:379) and develops a spatial memory deficit and enhanced synaptic plasticity in the form of long-term potentiation (LTP) by 16 weeks of age (Earls, et al. (2010) J. Neurosci. 30:15843). This age-dependent alteration in hippocampal synaptic plasticity is caused by an aberrant increase in the protein level of the sarco(endo)plasmic reticulum ATPase (SERCA2), which maintains calcium (Ca2+) levels in the endoplasmic reticulum (ER). SERCA2 upregulation leads to increased LTP by enhancing Ca2+ entry into presynaptic cytoplasm and releasing an excess of neurotransmitter during synaptic plasticity induction. Therefore, the age-dependent synaptic abnormalities in Df(16)1/+ mice may be relevant to the cognitive decline observed at the onset of schizophrenia. Identification of the culprit genes within the 22q11DS-critical region that cause these abnormalities provides insight into the pathophysiology of schizophrenia.
A survey of miRNA expression patterns in various organ and tissue types has identified several brain-specific and brain-enriched miRNAs (Sempere, et al. (2004) Genome Biol. 5:R13). There are a growing number of miRNAs with well-characterized neurodevelopmental functions. miR-124 and miR-9 influence the decision of neural precursors to adopt a neuronal or glial fate. miR-124 inhibits expression of nonneuronal genes and splicing factors, and transfecting miR-124 duplexes into progenitor cells decreases the number of cells expressing glial markers (glial fibrillary acidic protein) while increasing the number of neurons (Smirnova, et al. (2005) J. Neurosci. 21:1569-77). In addition, altered expression of selected miRNAs has been shown to correlate with schizophrenia or bipolar disorder (Moreau, et al. (2011) Biol. Psychiatry 69:188) and miRNAs, as well as proteins regulating the biogenesis of miRNAs (e.g., DGCR8), have been suggested for use in the diagnosis and prognosis of schizophrenia (US 2010/0227908 and US 2010/0009367).